Dr. Yao Zhu talks to Dr. Nguyen: Advances in Radiotherapy and Surgical Treatment of Prostate Cancer at ASCO-GU 2023

Urinary Surgery, Fudan University Shanghai Cancer Center

Radiation Oncology, Harvard Medical School

The 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium (ASCO-GU 2023) has concluded. During this conference, several studies related to early-stage/ localized prostate cancer radiotherapy or surgical treatment were presented as oral reports. Among them, the FORMULA-509 study presented by Dr. Paul L. Nguyen of the Dana-Farber Cancer Institute at Harvard Medical School showed that for high-risk patients with biochemical recurrence after radical surgery, combining 6 months of ADT (Androgen Deprivation Therapy) with novel hormonal therapy on top of salvage radiotherapy can improve patient survival. “Oncology Frontier” invited Dr. Zhu Yao from Fudan University Shanghai Cancer Center to have a discussion with Dr. Nguyen, delving into the interpretation of the FORMULA-509 study and other prostate cancer surgery and radiotherapy-related research presented at the conference.

Interpreting the FORMULA-509 Study

Significant Benefits for High-Risk Patients with PSA > 0.5

“Oncology Frontier”: First of all, congratulations to Dr. Nguyen for leading the FORMULA-509 study, which was selected for oral presentation at this year’s ASCO-GU. Could you please introduce the main results of this study for us? Additionally, Dr. Zhu Yao, how do you evaluate this study?

Dr. Nguyen : The FORMULA-509 study is a randomized controlled trial that enrolled 345 patients with prostate cancer who experienced an increase in PSA levels (≥0.1 ng/ml) after radical prostatectomy and had one or more high-risk factors (Gleason 8-10, PSA > 0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative surgical margins, persistent PSA elevation, extensive local/regional disease, high Decipher risk). These patients received either 6 months of GnRHa (Gonadotropin-Releasing Hormone agonist) plus bicalutamide (standard group) or GnRHa plus abiraterone or apalutamide (experimental group) on top of salvage radiotherapy (SBT) as the baseline treatment.

The research results showed that the primary endpoint, which is the PSA progression-free survival (PSA-PFS), was close to a statistically significant difference between the two groups, with a hazard ratio (HR) of 0.71 (90% confidence interval: 0.49~1.03), and a p-value of 0.06. Therefore, we only did not achieve significance on the one-sided p-value. However, subgroup analysis revealed a significant benefit in PSA-PFS (HR 0.50, 95% CI: 0.30~0.86, p=0.03) among patients with PSA > 0.5. Most importantly, the MFS (Metastasis-Free Survival) risk ratio in this subgroup of patients was only 0.32 (95% CI: 0.15~0.72), with a p-value of 0.02. The 3-year MFS rate with abiraterone and apalutamide treatment was increased by an absolute 18.2%, and the number needed to treat (NNT) was 5. This means that for every 5 patients treated, 1 case of metastasis could be prevented. We consider this to be a very favorable outcome, especially for patients with PSA > 0.5.

Dr. Zhu Yao: First of all, I would like to congratulate Dr. Nguyen on presenting such an impressive research report at the ASCO-GU conference. This study demonstrates a very strong signal that enhanced treatment with ADT and novel hormonal therapy on top of salvage radiotherapy can provide a survival benefit for high-risk patients with biochemical recurrence after radical surgery. In this trial’s two randomized groups, the control group received the standard hormonal therapy regimen, which is 6 months of ADT combined with bicalutamide, while the experimental group aimed to enhance androgen deprivation therapy (ADT) by using novel hormonal treatments such as abiraterone or apalutamide to maximize treatment efficacy. Although the overall significance was not achieved, subgroup analysis provides valuable information. We can see that in patients with PSA > 0.5, the 3-year MFS rate increased from 66.1% to 84.3%. This is indeed a significant improvement, and it’s surprising to see such substantial benefits within just 6 months of enhanced treatment. I believe these results are worth further validation in other trials.

Dr Nguyen: Thank you very much for your comments on this study, and you are correct that further validation is needed. In the RADICALS-HD study, 2 years of ADT showed a significant improvement in MFS compared to 6 months of ADT (HR 0.77, P=0.03). However, when we compare across studies, we can see that the MFS benefit from 6 months of ADT plus abiraterone/apalutamide in the FORMULA-509 study is even greater, with an HR of only 0.57, which is better than the HR of 0.77 in the RADICALS-HD study. Similar results are observed in the PSA > 0.5 subgroup, with an HR of 0.67 in the RADICALS-HD study and an HR of 0.32 in our study. From these two studies, it appears that for tumors with PSA > 0.5 or greater aggressiveness, if enhanced ADT treatment is considered, there may not be a need to extend ADT to 2 years as in the RADICALS-HD study. Instead, it may be sufficient to combine abiraterone/apalutamide with 6 months of ADT. Dr. Zhu Yao, how do you view this issue in your clinical practice?

Dr. Zhu Yao: I believe the information you provided is very important because we can see from the treatment of metastatic prostate cancer that early intensive treatment can bring survival benefits to patients. Your research advances intensive treatment from late-stage metastatic disease treatment to early-stage/localized salvage treatment, which is crucial for our practice and our patients. Using a 6-month intensive treatment as an alternative to 24 months of ADT treatment is feasible and can save patients a significant amount of treatment costs and reduce drug exposure. More importantly, it shows a strong signal of improved metastasis-free survival. I agree with your perspective that we can opt for shorter-term intensive treatment instead of long-term, continuous ADT treatment; prolonged ADT treatment for two to three years could indeed significantly impact a patient’s quality of life.

Dr Nguyen: Yes, we do aim to shorten the duration of treatment for patients. We will need to see the results of the PROSTATE-IQ study in the future, but I believe that 6 months of intensive treatment may offer better quality of life for patients compared to 2 years of ADT treatment.

Interpreting the TRIP Study

Is Longer ADT Duration Better?

“Oncology Frontier”: In fact, the PSA-PFS and MFS benefits in the ITT population of the FORMULA-509 study were already very close to significance. If the treatment duration were extended by a few months, would it yield a positive outcome? Looking at the RADICALS-HD study reported last year at ESMO, 24 months of ADT were more effective than 6 months of ADT; however, this year’s ASCO-GU report on the TRIP study showed that 30 months of ADT were not superior to 6 months of ADT. How do both of you view this issue?

Dr. Nguyen: The RADICALS-HD study targeted patients after radical surgery, and it showed that combining 24 months of ADT with radiotherapy improved MFS compared to 6 months of ADT. On the other hand, the TRIP study included patients (T2c-3a, PSA > 20 ng/ml, or Gleason score > 7) who were planned to undergo radiotherapy (including EBRT + brachytherapy), and they received either 6 months of ADT or 30 months of ADT on top of radiotherapy. The results showed that the longer course of ADT did not improve biochemical progression-free survival (9-year biochemical progression rates: 10.4% vs. 9.5%, p=0.647), which was unexpected. However, the radiotherapy regimen used in the TRIP study was very intensive, involving brachytherapy in addition to external beam radiotherapy (EBRT). Some opinions in the field of radiation oncology suggest that with such an intensive radiation approach using EBRT combined with brachytherapy, less hormonal therapy may be needed. Some meta-analyses and retrospective studies have indicated that with the strong local radiation doses from brachytherapy, patients may not require more than 12 months of hormonal therapy. Of course, this is still a hypothesis that needs validation in randomized controlled trials. The TRIP study should be the first randomized controlled trial to test this hypothesis. Interestingly, for patients undergoing surgery or ablation treatment, prolonging and intensifying hormonal therapy seems to be beneficial. These questions need further exploration, and for now, I would still choose standard treatment, hoping to see more data in the future.

Dr. Zhu Yao: Dr. Nguyen emphasized the difference in ADT treatment duration between the TRIP study and other studies, with the most crucial point being the very high radiation dose used in the TRIP study. Previous research has suggested that administering high-dose radiation to the primary tumor may improve disease control. I also want to highlight some other differences between the TRIP and FORMULA studies. When we compare the baseline characteristics of the two groups, we can see that in the TRIP study, less than 20% of patients had a Gleason score of ≥9, whereas in the FORMULA study, this proportion exceeded one-third. We know that a higher Gleason score indicates a more aggressive tumor. Therefore, ADT duration can be adjusted based on the risk characteristics of patients in clinical practice. For tumors with higher aggressiveness, a longer duration or more intensive hormonal therapy should be considered.

Another point is that there isn’t much data on ADT and treatment duration specifically for Asian populations. Our guidelines or clinical trials might need to differentiate treatment for Asian populations from Caucasian populations. Some small-scale studies conducted by our team suggest significant genomic differences in prostate cancer between Asian and Western populations. For example, many Asian prostate cancer patients have indolent tumors and may be very sensitive to ADT treatment. Additionally, the average age in the TRIP trial was 70 years, while it was 63 years in the FORMULA trial. There may be some differences in testosterone levels between older Asian men and younger Western men, which could potentially affect the trial outcomes, and this also needs further validation.

Dr. Nguyen: Dr. Zhu raised some excellent points. I completely agree with your perspective that older men who receive 6 months of hormonal therapy might need an additional 18 months of continuous suppression, and they could be the beneficiaries of 2-year hormonal therapy. I agree with your idea of stratifying patients based on risk to select for intensified treatment. Looking back at this study, approximately 50% of patients had Gleason scores of 8 to 10, which means the other half had Gleason scores of 6 or 7. Therefore, their risk was not particularly high; they were more like moderate risk. About 57% of patients had only one high-risk factor. So, perhaps we included a more favorable population in this study, which is why we didn’t see a benefit from extending ADT duration.

Interpreting the PACE-A Study

Urology and Radiation Oncology Head-to-Head PK

“Oncology Frontier”: Another study that attracted attention at this ASCO-GU conference was PACE-A, which compared SBRT (Stereotactic Body Radiotherapy) to surgical treatment for localized prostate cancer (LPCa) head-to-head. As experts in radiation oncology and urology, how do both of you view the SBRT vs. surgery question from the perspective of quality of life and oncological outcomes, considering that SBRT unsurprisingly outperformed surgery in terms of urinary control and sexual function?

Dr. Nguyen: This is a very important study, and of course, it has generated a lot of controversy. When I saw the results, I glanced at a urologist friend sitting next to me, and it was quite interesting. I’m very curious to hear what urologists have to say about this study. There are also some other studies looking at quality of life between radiation and surgery, but the results have not been released yet. Overall, the quality of life findings in this study are not different from what we saw in the ProtecT trial. Patients receiving radiation had worse gastrointestinal symptoms and urinary obstructive symptoms (though this is not the key point). In the PACE-A trial, SBRT was associated with less urinary incontinence and better sexual function compared to surgery, but worse gastrointestinal function. What I find truly surprising is that the surgical group had an unusually high absolute rate of urinary incontinence, approaching 50% (46.9% vs. 4.5%, p<0.001). Dr. Zhu, I would like to hear what urologists think about this.

Interpreting the PACE-A Study

Urology and Radiation Oncology Head-to-Head PK

“Oncology Frontier”: Another study that attracted attention at this ASCO-GU conference was PACE-A, which compared SBRT (Stereotactic Body Radiotherapy) to surgical treatment for localized prostate cancer (LPCa) head-to-head. As experts in radiation oncology and urology, how do both of you view the SBRT vs. surgery question from the perspective of quality of life and oncological outcomes, considering that SBRT unsurprisingly outperformed surgery in terms of urinary control and sexual function?

Dr. Zhu: I think the PACE-A study presents a challenge to the field of urology. There have been very few randomized controlled trials (RCTs) that directly compare radiation therapy to surgery head-to-head. We’ve been searching for answers to this question for years, and PACE-A takes the first step. While the sample size in the PACE-A study is relatively small, the results carry important messages. First, from a surgical perspective, we should pay attention to patient-reported outcomes (PROs), not just our own assessment of patient outcomes. In this study, the surgical treatment group had a high rate of urinary incontinence. So, as surgeons, we should ask ourselves whether we have overestimated the outcomes of surgical treatment. Should we evaluate patients’ rates of urinary incontinence more and work on improving our surgical skills?

Second, I think it’s important to compare surgery to radiation therapy because the outcomes of surgery are closely related to the surgeon’s technical skills. Looking at many multicenter RCTs on radiation therapy, the results are generally consistent. We should also learn from radiation oncologists how to design such RCTs, how to control the quality of surgery, and how to reduce unnecessary surgical complications further. We shouldn’t only evaluate surgeries performed at top-tier institutions like MD Anderson or MSKCC but also assess surgeries performed at community hospitals.

So, the two important messages I get from the PACE-A study are: first, prioritize PROs to improve patient outcomes, and second, learn from radiation therapy RCTs how to enhance the quality of radical surgery. These are the goals we urologists should strive to achieve.

Radiation Therapy vs. Surgery

Local Treatment Options for Oligometastatic mHSPC

“Oncology Frontier”: For oligometastatic prostate cancer, we know that Fudan University Affiliated Tumor Hospital has conducted a randomized controlled study on surgical treatment, and the results were reported at previous ESMO meetings. Could both of you share your views on whether surgery or radiation therapy should be chosen for local treatment of oligometastatic prostate cancer?

Dr. Zhu: Let me briefly introduce this study. In this research, we randomized patients with oligometastatic hormone-sensitive prostate cancer to receive either pure ADT treatment or ADT combined with radical treatment of the primary lesion (including surgery and radiation therapy). In approximately 3 years of follow-up, patients who had the primary tumor removed had better progression-free survival (NR vs. 50 months; HR 0.50, p=0.015) compared to patients who received ADT alone. I believe these results are consistent with the findings of the STAMPEDE study published in The Lancet. That study showed that radiation therapy to the primary tumor improved overall survival in low metastatic burden mHSPC patients. I’d like to hear Dr. Nguyen’s opinion on whether we should choose radiation therapy or surgery for local treatment of oligometastatic mHSPC. How do you approach this issue in your clinical practice?

Dr. Nguyen: This is a great study, a forward-looking randomized controlled trial, and it’s published in the European Urology Journal, so it’s well disseminated in the field. We know that it’s challenging to conduct randomized controlled trials comparing surgery with non-surgical approaches, and this study provides us with important insights. As you pointed out, there are data involving radiation therapy in the STAMPEDE study, but there are no randomized data on the value of surgery, and we are waiting for the results of the SWOG/NRG 1806 study. Your study has given us very important information.

When I encounter such patients in clinical practice, I usually tell them that there is level 1 evidence that radiation therapy is beneficial in terms of overall survival, but considering surgical treatment is also reasonable. Your study has shown a progression-free survival benefit with surgery. We do have patients who choose surgery. I explain to them which data support radiation therapy and which data support surgery, and each approach may have its advantages and disadvantages. The only question is, if radiation therapy can be beneficial, whether it sparks some kind of immune mechanism that leads to an escape effect of metastatic disease on the immune system in the absence of surgery. This could be an important difference between radiation therapy and surgery. In addition, ablation and surgical treatment have similar efficacy in local treatment. Congratulations on completing this very important study.

Dr. Zhu: Thank you for your affirmation. I also have a question about changing patterns of prostate cancer evaluation. When discussing all these issues, we use conventional evaluation methods provided by these trials. Nowadays, we have PSMA (Prostate-Specific Membrane Antigen), which can provide us with more accurate staging information and can be used for monitoring and detecting smaller lesions. How should we interpret PSMA PET scan results and, considering current evidence-based medicine, especially in newly diagnosed prostate cancer, how can we improve the treatment for these patients? Please share your clinical practice experience on this.

Dr. Nguyen: Most of our newly diagnosed high-risk patients undergo PSMA PET scans. I think we shouldn’t stop patients from receiving active treatment based on PSMA PET scan results. Suppose a patient has high-risk disease, and conventional imaging is negative, but PSMA PET shows metastatic lesions. In that case, I wouldn’t prevent the patient from receiving active local treatment or diagnostic treatment because there are indeed patients with small PSMA-positive lesions who benefit from this. If PSMA PET identifies focal lesions, we can use SBRT (Stereotactic Body Radiotherapy). For patients with PSMA-positive disease, we shouldn’t deny them active treatment.

Dr. Zhu: We share the same perspective. If patients have ≤5 metastatic lesions, we mainly treat them based on their high-risk localized disease. If patients have very extensive disease (although this is relatively rare even in high-risk patients), we would ask them to undergo systemic treatment rather than local treatment. At the very least, PSMA PET provides prognostic information, indicating that patients may have an aggressive disease.

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